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4-Aroylpiperidines and 4-(Α-Hydroxyphenyl)Piperidines As Selective Sigma-1 Receptor Ligands: Synthesis, Preliminary Pharmacolog

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4-Aroylpiperidines and 4-(Α-Hydroxyphenyl)Piperidines As Selective Sigma-1 Receptor Ligands: Synthesis, Preliminary Pharmacolog Ikome et al. Chemistry Central Journal (2016) 10:53 DOI 10.1186/s13065-016-0200-1 RESEARCH ARTICLE Open Access 4‑aroylpiperidines and 4‑(α‑hydroxyphenyl)piperidines as selective sigma‑1 receptor ligands: synthesis, preliminary pharmacological evaluation and computational studies Hermia N. Ikome1, Fidele Ntie‑Kang1,2* , Moses N. Ngemenya3, Zhude Tu4, Robert H. Mach4 and Simon M. N. Efange1* Abstract Background: Sigma (σ) receptors are membrane-bound proteins characterised by an unusual promiscuous ability to bind a wide variety of drugs and their high affinity for typical neuroleptic drugs, such as haloperidol, and their poten‑ tial as alternative targets for antipsychotic agents. Sigma receptors display diverse biological activities and represent potential fruitful targets for therapeutic development in combating many human diseases. Therefore, they present an interesting avenue for further exploration. It was our goal to evaluate the potential of ring opened spipethiane (1) analogues as functional ligands (agonists) for σ receptors by chemical modification. Results: Chemical modification of the core structure of the lead compound, (1), by replacement of the sulphur atom with a carbonyl group, hydroxyl group and 3-bromobenzylamine with the simultaneous presence of 4-fluorobenzoyl replacing the spirofusion afforded novel potent sigma-1 receptor ligands 7a–f, 8a–f and 9d–e. The sigma-1 receptor affinities of 7e, 8a and 8f were slightly lower than that of 1 and their selectivities for this receptor two to threefold greater than that of 1. Conclusions: It was found that these compounds have higher selectivities for sigma-1 receptors compared to 1. Quantitatitive structure–activity relationship studies revealed that sigma-1 binding is driven by hydrophobic interactions. Keywords: Sigma-1 binding, Piperidines, QSAR, Pharmacophore Background pharmacological entity distinguished by an unusual pro- Sigma (σ) receptors are membrane-bound proteins miscuous ability to bind a wide variety of drugs [3]. Ini- that bind several psychotropic drugs with high affinity tial interest in σ receptors came mainly from their high [1]. They were initially proposed to be related to opi- affinity for typical neuroleptic drugs, such as haloperidol, oid receptors [2] but were later found to be a distinct and their potential as alternative targets for antipsychotic agents [4, 5]. However, no endogenous functional ligand (agonist) for σ receptors has been conclusively identified. *Correspondence: [email protected]; [email protected] These receptors are classified into two subtypes: sub- 1 Department of Chemistry, Faculty of Science, University of Buea, P.O. Box 63, Buea, South West Region, Cameroon type 1 (σ1 receptor) and subtype 2 (σ2 receptor) which 2 Department of Pharmaceutical Chemistry, Martin-Luther University are differentiated by their pharmacological profiles, dis- of Halle-Wittenberg, Wolfgang‑Langenbeck‑Str. 4, 06120 Halle (Saale), tribution in tissues, functions, and molecular sizes [6], Germany Full list of author information is available at the end of the article with the σ1 being the most documented. Basically, the © 2016 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ikome et al. Chemistry Central Journal (2016) 10:53 Page 2 of 15 σ1 receptor is believed to have a ligand binding profile dealing with several cancer cell types through a variety of such that (+)-benzomorphans are at least fivefold to ten- strategies [23]. A typical endogenous σ1 receptor regula- fold more potent than their corresponding (−)-isomers tor is the hallucinogen N,N-dimethyltryptamine [24]. [7]. On the other hand, for the σ2 subtype, the (−)-ben- Moreover, σ1 receptor ligands have recently been shown zomorphans are more potent than their corresponding to be potent noncompetitive antagonists at the N-methyl- (+)-isomers in the binding assay. The gene coding the d-aspartate (NMDA) receptor with IC50 values similar to σ1 receptor has been isolated and cloned from guinea those of the dissociative anesthetic (S)-(+)-ketamine [25]. pig [8], mouse [9], rat [10], and human [11]. The protein Ghandi et al. recently carried out a one pot synthesis of coded by the σ1 receptor gene in rat brain consists of a new spirocyclic-2,6-diketopiperazine derivatives, with 223 amino acid sequence (23 kDa). In contrast, the σ2 benzylpiperidine and cycloalkane moieties, some of which receptor has not been cloned yet and is estimated to have showed up to a 95-fold σ1/σ2 selectivity ratio [26]. a molecular weight of 19–21.5 kDa [12]. The presence of Over the years, a large number of compounds with a σ3 subtype has not been confirmed yet, even though its unrelated chemical structures have been reported to dis- existence was proposed in a few papers [13–15]. play affinity for σ receptors (Fig. 1). To explain the bind- The specific participation and character of σ receptors ing of these structurally diverse compounds to sigma in the processes of the psychiatric and neurological dis- receptors, a number of models or pharmacophores have orders is still not clear [16]. Nevertheless, some of the been proposed [13, 27–33]. Generally, the pharmacoph- ligands have drawn attention as potentially useful antip- ore (ph4) for σ1 receptor binding consists of three major sychotics, antidepressants [17, 18], anxiolytics [19], anti- sites: an amine site as an essential proton acceptor site, amnesics, for mental improvement [20], analgesics [21], flanked by two hydrophobic domains, a primary hydro- anti-epileptics, anticonvulsants, and as seizure reducing phobic site that binds phenyl group “B” from the central neuroprotective agents [22]. Apart from their involvement amine and a secondary binding site that binds phenyl in psychiatric disorders and nervous system diseases, σ group “A” from the central amine (Fig. 2). Gund and cow- receptors and their ligands offer a plethora of means for orkers [13] suggested that the chains between the amine OH S N N spipehthiane (1) (+) pentazocine (2) F Cl N O OH N N OH N N F F haloperidol (3) BMY 14802 (4) NH N N H H ditolylguanidine (5) Fig. 1 Some sigma receptor ligands Ikome et al. Chemistry Central Journal (2016) 10:53 Page 3 of 15 Amine site attracted to spipethiane (1), a spirocyclic compound that contains the elements of benzylpiperidine. Spipethiane is A N s/o B a very potent and selective ligand for σ1 receptors (Ki: σ1, Secondary Secondary binding site Primary hydrophobic 0.5 nM; σ2, 416 nM) [34]. The design of this compound hydrophobic site site was inspired by the reported high affinity of the spirote- Fig. 2 Gund’s pharmacophore model tralins (2) for σ1 receptors. In contrast to the spirotetra- lins, spipethiane does not display high affinity for 5-HT2 receptors. Consequently, the compound was one of the site and aromatic rings need not be simple alkyl chains. most selective σ1 ligands reported at the time. Since this They could bear a polar substituent such as S or O, which initial discovery, the work on this spirocyclic skeleton could be considered as the second binding site (Fig. 3). has been extended to include several compounds which Other functional groups can be piperidyl, guanidinyl, are reported to display high affinity and selectivity for1 σ pyrrolidyl, piperazyl, thiochromanyl, and benzamidyl [7]. receptors, and potential antitumor activity [33, 35]. Spi- A pharmacophore for σ2 binding has also been proposed pethiane and it analogues therefore provide interesting [24, 30–33]. The latter is also characterized by a central targets for further investigation. amine site flanked by two hydrophobic sites. However, Deprived of conformational freedom, spirocyclic com- the two models (σ1 and σ2) differ in a number of respects, pounds such as spipethiane and the spirotetralins may such as the distance between the central amine site and derive their receptor selectivity from their ability to the hydrophobic sites [13, 32]. adopt only a restricted number of molecular conforma- Owing to the apparent involvement of σ receptors in a tions. The current study sought to investigate the role of variety of biological processes, and the potential applica- spirofusion in the biological activity of the spipethiane/ tions of σ ligands in pharmacology and medicine, interest spirotetralin skeleton. The compounds obtained from the in these receptors and their ligands has remained high, study were tested for binding to σ1 and σ2 receptors. and there is a continuing search for new selective ligands that can serve either as agonists or antagonists at those Results and discussion biological processes that are mediated by σ receptors. Compounds 7a–f, 8a–f and 9d–e were synthesized Among the compounds reported to bind σ receptors, according to methods A–C reported in Scheme 1. Reac- a large number of benzylpiperidine and benzylpipera- tion of 4-(4-fluorobenzoyl)piperidine with various substi- zine derivatives display remarkable affinity. In review- tuted benzyl halides in the presence of sodium acetate, in ing these collections of
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